Oxygenated macrocycles having 12-16 atoms are valuable fragrance ingredients, e.g., 3,4,5,6,7,8,9,10,11,12,13,14-dodecahydro-2H-cyclododeca[b]pyran (BCP; also named 13-oxabicyclo[10.4.0]hexadec-1(12)-ene) and Exaltolide. These compounds are typically manufactured through the common intermediate keto-alcohol as shown in Scheme 1 below.

Four different routes have been described in the literature for the synthesis of this intermediate, and subsequently of the target two products.
A first reported route utilizes tert-butyl peroxide in an amount of 15-30 mol % to obtain the keto-alcohol intermediate in a batch reaction with a yield below 25% based on the amount of the starting material cyclododecanone added to the reaction mixture. See U.S. Pat. No. 3,856,815. This process operates at high temperatures (>135° C.) to achieve a reasonable yield. Further, the reactants must be carefully added to the reaction mixture at such a rate that the decomposition of the peroxide and the synthetic reaction couple well, resulting in a low reproducibility of the yield from batch to batch.
A second route involves a cyclization between an imine group and an adjacent alkyl ester group on a dodecane ring with lithium aluminum hydride at a yield of 50%. See Mahajan et al., Synthesis 1980, 1, 64-6. Lithium aluminum hydride is an expensive reagent, which is harmful to the health of plant operators, is explosive during work-up with water, and generates a large amount of hazardous solid waste. As such, the use of the aluminum agent is not cost effective, particularly on a large scale.
A third route follows a three-step process including (i) ketal protection of the ketone, (ii) partial ketal opening with an aluminum reducing agent, and (iii) cyclization with a strong acid to obtain the oxygenated macrocyle product with a yield of 10% or below. For step (iii), see Gassman et al., J. Org. Chem. 1993, 1449-57. The yield from this route is low and the use of the aluminum agent is not cost effective.
A fourth route, illustrated in Scheme 2 below, also includes three steps: (i) preparation of a spiroacetal from dodecanone and a 1,3-diol in the presence of a catalytic amount of p-toluenesulfonic acid or pyridinium p-toluenesulfonate, (ii) obtaining a hydroxyl vinyl ether by deprotonation and ether cleavage of the spiroacetal using triisobutylaluminum, and (iii) forming the oxygenated macrocycle by annulation-elimination of the hydroxyl vinyl ether. See Hanaki et al., Tetrahedron 1996, 52(21), 7297-7320. Apart from the low yield, the route is not cost effective as it uses triisobutylaluminum.

Among the methods described above, only the first one utilizes a one-step synthetic process to prepare the target fragrance compounds. Nevertheless, it requires the consumption of a large amount of hazardous di-tert-butyl peroxide.
There is a need to develop a cost effective, safe process of preparing an oxa-bicyclo alkene in a reasonable yield.